Esterified bromoacetanilides

ABSTRACT

Esterified bromoacetanilides as new compositions of matter and their activity as microbiocides. Representative compounds include 3&#39;&#39;-bromoacetoxy bromoacetanilide, 3&#39;&#39;-acetoxy bromoacetanilide, 3&#39;&#39;-propionoxy bromoacetanilide, 3&#39;&#39;-(p-methylbenzoxy) bromoacetanilide, 3&#39;&#39;-cyclohexane carbonyloxybromoacetanilide.

United States Patent 1191 Baker et al.

[ Aug. 5, 1975 1 ESTERIFIED BROMOACETANILIDES [75] Inventors: Don R. Baker, Orinda; Eugene G.

Teach, El Cerrito, both of Calif.

[73] Assignee: Stauffer Chemical Company,

Westport, Conn.

[22] Filed: Nov. 30, 1972 [21] Appl. No.: 311,034

Related U.S. Application Data [60] Continuation-impart of Ser. No. l27 760, March 24, 1971, abandoned, which is a division of Ser. No. 806,717, March 12, 1969 abandoned.

[56] References Cited UNITED STATES PATENTS 3.032.555 5/1962 Oxley et all 260/268 Strycker 260/562 Olin 260/562 B OTHER PUBLICATIONS Noguchi et al., Yakugaku Zasshi, Vol. 88, pp. 1620-1637, (1968).

Adams et al., J. Chem. Eng. Data, Vol. 12, pp. 619-621, (1967).

Ozawa et al., Yakugaku Zasshi, Vol. 73, pp. 719-721,(1953).

Primary Examiner-Lorraine A. Weinberger Assistant Examiner-Michael Shippen Attorney, Agent, or Firm-Harry A. Pacini; Daniel C. Block; Edwin H. Baker 5 7 ABSTRACT Esterified bromoacetanilides as new compositions of matter and their activity as microbiocides. Representative compounds include 3 -bromoacetoxy bromoacetanilide, 3'-acetoxy bromoacetanilide, 3'- propionoxy bromoacetanilide, 3'-(p-methylbenzoxy) bromoacetanilide, 3 -cycl0hexane carbonyloxybromoacetanilide.

4 Claims, No Drawings ESTERIFIED BROMOACETANILIDES C E-CH Br wherein R, is hydrogen or lower alkyl having from 1 to about 4 carbon atoms, inclusive, R represents (1) hydrogen;

in which R,, is alkyl, phenyl, substituted-phenyl in which the substituents are chloro, nitro, lower alkyl, lower alkoxy or cyano;

in which R is alkyl, phenyl, substituted-phenyl in which the substituents are chloro, nitro, lower alkyl, lower alkoxy or cyano;

in this R is hydrogen, alkyl, cyclohexyl, haloalkyl, phe nyl, substituted phenyl in which the substituents are chloro, nitro, lower alkyl, lower alkoxy or cyano; provided that when R hydrogen and R is hydrogen, then the group 1 ilTjSf'flHfi is substitued in the meta-position; and provided that when R is then the group is in the meta-position. The above compounds as well as compounds in which R is hydrogen and R is hydrogen and is in the para-position, are effective microbiocides.

' In the above description, the following preferred embodiments are intended for the various groups. Alkyl preferably includes, unless otherwise provided for, those members which contain from 1 to about 6 carbon atoms, inclusive, in both straight chain and branched chain configurations, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, sec.-butyl, amyl, isoamyl, nhexyl, isohexyl, and the like; and lower alkoxyalkyl preferably includes those members which contain a total of not more than 6 carbon atoms, for example, methoxymethyl, methoxyethyl, ethoxymethyl, methoxypropyl, ethoxypropyl, propoxypropyl, ethoxybutyl, methoxyamyl, and the like. Haloalkyl preferably includes those alkyl members which contain from 1 to about 4 carbon atoms, inclusive, and are substituted with at least one halogen such as chlorine, bromine and iodine. Lower alkyl and lower alkoxy preferably include those members which contain from 1 to about 4 carbon atoms, inclusive, in either straight chain or branched chain configurations.

' The compounds herein described can be prepared by one of several methods, depending upon the nature of the starting materials and products desired. The compounds 3'-hydroxybromoacetanilide within the scope of this invention can be conveniently prepared by the condensation of m-aminophenol and bromoacetyl bromide. This preparation is specifically described in Example l' below. Starting with either the 3'- or 4'- hydroxybromoacetanilide, subsequent condensation reactions can be performed which will ultimately yield other members of this series. Generally, these reactions are performed in a suitable solvent, such as benzene, toluene, acetone, methylethyl ketone and the like. The

atives disclosed herein, preferably when R, and R, are

both hydrogen, are prepared by conversion of the substituted-phenol to the corresponding chloroformate using phosgene, followed by reaction with the appropriate primary or secondary amine or ammonia. The preparation of the sulfonate, dialkyl carbamate, carbonate and carboxylate derivatives are prepared using the appropriate acid halide and an acid acceptor such as pyridine, triethylamine, sodium bicarbonate and the like. After the reaction is completed, the solvent is removed and the product recovered therefrom. Upon isolation of the crude product, final recovery of the purified material is accomplished by normal workup procedures, such as crystallization or distillation.

It has been found that the compounds as defined supra are effective bacteriostatic and fungistatic agents. Whereas microbiological growths on various substances cause deterioration by the presence of the infestation, the application of an agent to retard this adverse growth is desired. Such substances liable to fungus and bacterial infection include cloth, leather, paint, soaps, paper, wood, plastic, oil, and the like. it is contemplated herein that the microbiocidal compositions of the present invention may be effectively incorporated or applied to any of the substances susceptible to microbiological growths.

For maximum effectiveness, the active ingredients of the present invention are admixed in microbiostatically effective amounts with an inert adjuvant. In order to provide formulations particularly adapted for ready and efficient application to the materials to be treated, such formulations comprise those of both the liquid and solid types as well as the aerosol type formulations. Application can be directly to the substance to be protected from fungus and bacterial growth. In the pure state, the active ingredient may be too effective or too potent in some applications to have practical utility. A convenient method of treating cloth is by formulating the active ingredient with a soap or detergent and thereby imparting antiseptic or microbiocidal properties to the cloth as it is washed therewith.

For most effective protection it is preferred to apply the materials in intimate contact but thoroughly dispersed on or nearly in the surface to be protected. Therefore, the active ingredients have incorporated therewith a relatively inert agent or adjuvant as a dispersing medium, utilizing methods well known to those skilled in the art.

Suitable formulations of the compounds of this invention comprise the above-defined active ingredients and a suitable material as an adjuvant therefor. Fungistat and bacteriostat compositions are advantageously formulated by first preparing a solution thereof in an organic solvent and then adding the resulting solution to water or other carrier. If necessary, an emulsifying agent may be employed. The compositions may also be incorporated into solid carriers such as clay, talc, pumice, soap, and the like. They may also be dissolved in liquefied gases such as fluorochloroethanes or methyl chloride and applied from aerosol bombs containing the solution. It should be noted that suitable, formulations may also include adhesive agents, indicators, and

other microbiocidal ingredients. Other ingredients may be supplementary insecticides, fungicides, bacteriocides, nematocides or selective herbicides.

Since the amount of active agent of the present invention which is employed will vary with the microbiocidaleffect sought, the utility of the treated material, type and dimensions .of the material treated, his evident that no rigid limits can be set forth on the quantity required. Determination of the optimum effective concentration for a specific performance is readily ascertainable by routine procedures, as will be apparent to those skilled in the art.

Preparation of the compounds of the present invention are illustrated by the following particular examples. Following the examples is a table of compounds which are prepared according to the procedures described herein.

EXAMPLE 1 Preparation of 3'-hydroxybromoacetanilide.

m-Aminophenol, 66.5 g. (0.61 mole), is dissolved in 500 ml. of a 50/50 (v/v) mixture of glacial acetic acid and saturated sodium acetate solution. The mixture is cooled to approximately 10C. and 200 g. (0.99 mole) of bromoacetyl bromide is added dropwise. The temperature is maintained between 15 and 20C. When addition is complete, the mixture is stirred while cooling until the temperature is about 5C. The product is filtered off, washed successively with cold water, saturated sodium bicarbonate solution and finally two portions of water. The product is dried under vacuum. The yield of the title compound is 121 g. (86 per cent of theory), m.p. l67-l70C.

EXAMPLE ll Preparation of 3'-N-methyl carbamoyloxy bromoacetanilide.

- lizes from solution and is recovered by filtration. There is obtained 24 g. (56 per cent of theory) of the title compound. m.p. l36-l38C.

EXAMPLE m Preparation of 3-propionoxy bromoacetanilide.

The anilide, 3-hydroxy bromoacetanilide, 6.9 g. and propionyl chloride (3.1 g., 0.033 mole) are combined in 120 ml. of methylene chloride as a solvent. Pyridine (2.6 g., 0.033 mole) is added dropwise. A slightly exothermic reaction takes place during the addition. Stirring is continued at room temperature for 20 minutes. A clear solution is obtained. The material is washed sucessively with water, dilute hydrochloric acid and again with water. The organic layer is dried over anhy- 'clrous magnesium sulfate and the solvent evaporated. The resulting material is recrystallized from a mixture of ethylacetate and ether. There is obtained 6.5 g. of the title compound, m.p. 88C.

EXAMPLE lV Preparation of 3'-bromoacetoxy bromoacetanilide.

. Meta-aminophenol, 5.5 g., 0.05 mole, is held in suspension in 200 ml .'methylene chloride solvent. To this solution is added 20.2 g. (0.1 mole) bromoacetyl bromide. The mixture is cooled to about 5C. Pyridine is added dropwise and the temperature is maintained between 5-lOC. Upon completion of the addition, the reaction mixture is allowed to come to room temperature. At room temperature the solution clarifies. Stirring is continued for 1-2 hours to insure total reaction. The solution is washed successively with water, slightly acid wash (l-lCl) and water. After drying the organic In a similar manner as Example III, 6.9 g. of 3'- hydroxy bromoacetanlide was reacted with 2.8 g. acetyl chloride in l2O ml. of chloroform as solvent. Triethylamine, 3.6 g., was used as the base. The resulting product was washed with water, twice with sodium bicarbonate solution and twice with water. After drying over anhydrous magnesium sulfate and evaporating the solvent, there is obtained 9.0 g. of the title compound, layer over anhydrous magnesium sulfate. the solvent is 10 mp. 7982C.

TABLE 1 C-CH Br m.p. C. COMPOUND R R NUMBER 1 2 Position 1) 1 H H meta 167-170 2 H C(O)NHCH meta 136-138 3 H C(O)I I'HCH(CH meta 1&4-149 4 H C (O)NHCH CH=CH meta 122-125 5 H C (O)NH(cyc1ohexy1) meta 163-165 6- H H para 1419144 7 H C(O)CH Br meta 96-98 8 H C(O)CH CH meta 85-88 9 H C(O)-(p-CH -pheny-1;)"- meta 165-168 10 H C(O)cyclohexy1 meta 111-113 11 a c (0)0H meta 79-82 evaporated. The obtained solid is washed with pentane. 50

There is obtained 19.1 g. of the title compound, m.p. 96-98C.

TABLE V Preparation of 2'-acetoxy bromoacetanilide.

COMPOUND NUMBER Other examples ofxcompounds falling within the generic formula presented herein, which are preparable by the aforedescribed procedures and which may be formulated into microbiocidal compositions and applied as herein illustrated, are:

COMPOUND R R I Y NUMBER l 2 POSiIZ-LOH 49 c n 0(0) I f 50 0 11 c(o)c: n- 5; 51 0 11 c (O)CH I 1 52 0 11 s (O )pheny1 i 53 n s(o -c'1- hen 1) e t a 54 C 11 S (0 (r n -Cl-phenyl E 55 H S (0 (r n -NO -phenyl) IE2 56 H S (0 CH -phenyl) u i ea 57 n s(o L-CH O- heny1) ggia; 58 11-0 11 s(o )(g CN- hen 1) U 1 59 H S(O )(p -Br-pheny1) 1 33 60 n c o oheny1 i @291 61 i-C H C (0)0(g-C1-phenyl) p a a 62 a C(0)0(r p -N0 -pheny1) I w 63 CH C (0)O( -CH -phen'y1) meta 64 H C (0)O( -CH O-phenyl) meta 65 CH C(O)0(g-CH -pheny1) g 66 0 11 c (o)0( -p 21a 67 CH C(O)CH CH C1 meta 68 H C (O) -R-Cl-pheny1 ari 69 CH C(O) -t I .-NO -phenyl meta 70 C 11 C (0) -CH phenyl 52 71 H C (O -CH 0-pheny1 3 3 72 SR C (O)g-CN-phenyl meta 73 H C (0) -pheny1 eta 74 C H C (0) -pheny1 2 75 C H C(0)NH(cyc1ohexyl) pa ra 76 H C(O)NH(2-CN-phenyl) IE3 77 n-C H C(O)NH (p -CN-pheny1) let a 78 H C (O) NH (p -CH 0-pheny1) 313 79 H C(0)NH( -QH O-pheny1) 2525 80 CH C(O)NH'( Q-CH -phenyl rn et As previously mentioned, the herein described comlnVitro Vial Tests. pounds are microbiostatic agents which arc useful and 65 valuable in controlling fungi and bacteria. The com- The compounds are tested to determine the microbipounds of this invention are tested as microbiocides in t ic a y when in Contact with g ng fungi or the following manner. bacteria in an artificial medium. For each candidate compound. four l-ounce vials are partially filled, two with malt broth and two with nutrient broth.' The compound to be tested is placed in the vials at the desired concentration (expressed in parts per million). The vials containing malt broth are inoculated with water suspensions of spores of the desired fungi, Aspergillus niger and Penicillium italicum, and cells of the bacteria, Escherichia coli and Staphylococcus aureaus, are inoculated into the vials containing nutrient broth (one specie of organism per vial). The vials are then sealed and held for one week, after which time the growth of the organisms is observed and noted. The tests are repeated using lower concentrations of the candidate compounds to determine the lowest concentration that can be used and still offer some control of the growth of the organism. Table ll shows the results of the in Vitro tests.

( =lndicates partial control at this concentration. A Chloro/analog of Compound Number I. B Chloro/analog of Compound Number 3.

Soap Plug Test.

Samples of Compounds No. l and 3, and 3,4,4- trichlorocarbanilide (TCC) are incorporated at a level of 1% in sodium stearate using acetone with the slurry. 45

The products are air dried and pressed in a metal tube to form a soap plug approximately mm. in diameter and 2 mm. thick. These are placed on nutrient agar plates that have been streaked separately with Escherichia coli and Staphylococcus aureaus cells. The plates are incubated at 37C. for l7 hours. The radius of the zone of biological inhibition around the soap plug is measured. The data from this test are as follows:

TABLE Ill Soap Plug Test Zone of Biological Inhibition (mm) Samples ofCompounds No. l and 3 of 10-20 mg. are dissolved in 5 ml. of acetone and added to weighed amounts of a commercial laundry detergent identified as Tide", a trademark owned by Proctor and Gamble (a mixture of lauryl sulfate and alkyl benzenesulfonate with tripolyphosphate as a binder), to give a concentra- 'tion of 0.2%. in the detergent. From these detergent samples, l g. is added to 500 ml. of 50C. tap water. To this wash solution is added 25 g. of laundered white cotton duck and the mixture agitated by stirring for 10 minutes. The cloth samples are hand wrung and each sample twice rinsed with stirring for 10 minutes in 500 ml. of 50C. tap water. Thereafter, the cloth samples are hand wrung and air dried. Samples (1 inch square approximately) of the treated cloth samples are placed on nutrient agar plates that have been separately streaked with Staphylococcus aureus, Escherichia coli, Brevibacterium ammoniagenes, and Trichophyton mentagrophytes.

The following controls are included in this test: A blank and a control containing a commercial laundry detergent identified as Dreft, a trademark owned by Proctor and Gamble (active ingredients are sodium doderyl-benzene sulfonate, sodium perborate), which contains the biocide 3,3,4-trichlorocarbanilide (TCC). The plates are incubated at 37C. for various lengths of time to provide growth for the organisms at which time the zone of biological inhibition around the cloth samples is measured. The radius of the zone of biological inhibition around the cloth samples are reported in the following Table IV.

TABLE IV Detergent Formulation Test Zone of Biological inhibition (mm) Escher- SlaphyI- Trichophywn ichia ococcus Brevibacterium menlagru- Sample coli uureus ammoniagenes phytes Blank 0 0 O 0 Di-aft" Control 0 trace l 0 Compound No. l 2 3 0 l Compound No. 3 O l 2-3 0 What is claimed is: l. A compound having the formula 0R ll H l c -cu Br wherein R is hydrogen or lower alkyl having from 1 to 4 carbon atoms, inclusive, R represents bon atoms, inclusive.

2. A compound according to claim 1 in which R is bromomethyl, R is hydrogen and 13 14 is in the meta-position. is in the meta-Position 3 A compound according to caim 1 in which Rv is 4. A compound accordmg to claim 1 in which R is ethyl. R is hydrogen, and methyl, 1 15 y g n and -CH Br is in the meta-position. l0 =i 

1. A COMPOUND HAVING TE FORMULA
 2. A compound according to claim 1 in which RC is bromomethyl, R1 is hydrogen and
 3. A compound according to claim 1 in which RC is ethyl, R1 is hydrogen, and
 4. A compound according to claim 1 in which RC is methyl, R1 is hydrogen and 